Detecting and correcting for changes to an analyte indicator

ABSTRACT

A sensor, system, and method for detecting and correcting for changes to an analyte indicator of an analyte sensor. The analyte indicator may be configured to exhibit a first detectable property that varies in accordance with an analyte concentration and an extent to which the analyte indicator has degraded. The analyte sensor may also include a degradation indicator configured to exhibit a second detectable property that varies in accordance with an extent to which the degradation indicator has degraded. The analyte sensor may generate (i) an analyte measurement based on the first detectable property exhibited by the analyte indicator and (ii) a degradation measurement based on the second detectable property exhibited by the degradation indicator. The analyte sensor may be part of a system that also includes a transceiver. The transceiver may use the analyte and degradation measurements to calculate an analyte level.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of priority to U.S.Provisional Application Ser. No. 62/487,289, filed on Apr. 19, 2017,which is incorporated herein by reference in its entirety.

BACKGROUND Field of Invention

The present invention relates generally to detecting and correcting forchanges to an analyte indicator. Specifically, the present invention mayrelate to detecting and correcting for oxidation-induced degradation ofan analyte indicator in an analyte monitoring system.

Discussion of the Background

Analyte monitoring systems may be used to monitor analyte levels, suchas analyte concentrations (e.g., glucose concentrations). One type ofanalyte monitoring system is a continuous analyte monitoring system. Acontinuous analyte monitoring system measures analyte levels throughoutthe day and can be very useful in the management of diseases, such asdiabetes.

Some analyte monitoring systems include an analyte sensor, which may beimplanted (fully or partially) in an animal and may include an analyteindicator. The analyte sensor may lose sensitivity while implanted inthe animal as a result of changes in sensitivity parameters (e.g.,calibration constants). The changes in sensitivity parameters may be dueto, for example, degradation of the analyte indicator. The degradationmay be caused by, for example, oxidation of the analyte indicatorinduced by cellular generated reactive oxygen species (ROS). See, e.g.,U.S. Pat. No. 8,143,068, U.S. Pat. No. 9,427,181, and U.S. PatentApplication Publication No. 2012/0238842, each of which are incorporatedby reference herein in their entireties. The rate in vivo sensitivityloss can be reduced by, for example, using oxidation resistant indicatormolecules, integrating catalytic protection, and/or using a membranethat catalyzes degradation of reactive oxygen species (ROS). However,the reducing the rate of in vivo sensitivity loss does not completelyprevent sensitivity loss. The gradual change in sensitivity parametersover time may negatively affect analyte sensing accuracy and maynecessitate re-calibrations using reference analyte measurements (e.g.,self-monitoring blood glucose measurements), which may be uncomfortableand/or otherwise undesirable for a user.

SUMMARY

The present invention overcomes the disadvantages of prior systems byproviding an analyte monitoring system capable of detecting changes toan analyte indicator and correcting for the detected changes. Incontrast with prior art systems that can only correct for changes to ananalyte indicator at the time of a re-calibration that uses a referenceanalyte measurement, the analyte monitoring system may provide, amongother advantages, the ability to correct for changes to the analyteindicator without the need for a reference analyte measurement. In someembodiments, the analyte monitoring system may include an analyte sensorthat measures changes to the analyte indicator indirectly using adegradation indicator, which may by sensitive to degradation by reactiveoxygen species (ROS) but not sensitive to the analyte. In someembodiments, the degradation indicator may have optical properties thatchange with extent of oxidation and may be used as a reference dye formeasuring and correcting for extent of oxidation of the analyteindicator. In some embodiments, the analyte monitoring system maycorrect for changes in the analyte indicator using an empiriccorrelation established through laboratory testing.

One aspect of the invention may provide an analyte sensor formeasurement of an analyte in a medium within a living animal. Theanalyte sensor may include an analyte indicator, a degradationindicator, and sensor elements. The analyte indicator may be configuredto exhibit a first detectable property that varies in accordance with(i) an amount or concentration of the analyte in the medium and (ii) anextent to which the analyte indicator has degraded. The degradationindicator may be configured to exhibit a second detectable property thatvaries in accordance with an extent to which the degradation indicatorhas degraded. The extent to which the degradation indicator has degradedmay correspond to the extent to which the analyte indicator hasdegraded. The sensor elements may be configured to generate (i) ananalyte measurement based on the first detectable property exhibited bythe analyte indicator and (ii) a degradation measurement based on thesecond detectable property exhibited by the degradation indicator.

In some embodiments, the extent to which the degradation indicator hasdegraded may be proportional to the extent to which the analyteindicator has degraded. In some embodiments, degradation to the analyteindicator may include reactive oxidation species (ROS)-inducedoxidation, and degradation to the degradation indicator includesROS-induced oxidation. In some embodiments, the analyte indicator may bea phenylboronic-based analyte indicator. In some embodiments, thedegradation indicator may be a phenylboronic-based degradationindicator.

In some embodiments, the analyte sensor may further include an indicatorelement comprising the analyte indicator and the degradation indicator.In some embodiments, the analyte indicator may include analyte indicatormolecules distributed throughout the indicator element, and thedegradation indicator may include degradation indicator moleculesdistributed throughout the indicator element. In some embodiments, thesecond detectable property does not vary in accordance with the amountor concentration of the analyte in the medium.

In some embodiments, the sensor elements may include a first lightsource and a first photodetector. The first light source may beconfigured to emit first excitation light to the analyte indicator. Thefirst photodetector configured to receive first emission light emittedby the analyte indicator and output the analyte measurement. The analytemeasurement may be indicative of an amount of first emission lightreceived by the first photodetector. In some embodiments, the sensorelements may include a second light source and a second photodetector.The second light source may be configured to emit second excitationlight to the degradation indicator. The second photodetector may beconfigured to receive second emission light emitted by the degradationindicator and output the degradation measurement. The degradationmeasurement may be indicative of an amount of second emission lightreceived by the second photodetector. In some embodiments, the firstphotodetector may be configured to receive second excitation lightreflected from the indicator element and output a first reference signalindicative of an amount of reflected second excitation light received bythe first photodetector. In some embodiments, the sensor elements mayinclude a third photodetector configured to receive first excitationlight reflected from the indicator element and output a second referencesignal indicative of an amount of reflected first excitation lightreceived by the third photodetector.

Another aspect of the invention may provide a method including using ananalyte indicator of an analyte sensor to measure an amount orconcentration of an analyte in a medium. The method may include using adegradation indicator of the analyte sensor to measure an extent towhich the degradation indicator has degraded. The method may includeusing a sensor interface device of a transceiver to receive from theanalyte sensor an analyte measurement indicative of the amount orconcentration of the analyte in the medium. The method may include usingthe sensor interface device of the transceiver to receive from theanalyte sensor a degradation measurement indicative of the extent towhich the degradation indicator has degraded. The method may includeusing a controller of the transceiver to calculate an extent to whichthe analyte indicator of the analyte sensor has degraded based at leaston the received degradation measurement. The method may include usingthe controller of the transceiver to adjust a conversion function basedon the calculated extent to which the analyte indicator has degraded.The method may include using the controller of the transceiver tocalculate an analyte level using the adjusted conversion function andthe received analyte measurement. The method may include displaying thecalculated analyte level.

Still another aspect of the invention may provide an analyte monitoringsystem including an analyte sensor and a transceiver. The analyte sensormay include an analyte indicator, a degradation indicator, sensorelements, and a transceiver interface device. The analyte indicator maybe configured to exhibit a first detectable property that varies inaccordance with (i) an amount or concentration of an analyte in a mediumand (ii) an extent to which the analyte indicator has degraded. Thedegradation indicator may be configured to exhibit a second detectableproperty that varies in accordance with an extent to which thedegradation indicator has degraded. The sensor elements may beconfigured to generate (i) an analyte measurement based on the firstdetectable property exhibited by the analyte indicator and (ii) adegradation measurement based on the second detectable propertyexhibited by the degradation indicator. The transceiver may include asensor interface device and a controller. The controller may beconfigured to: (i) receive the analyte measurement from the analytesensor via the transceiver interface device of the analyte sensor andthe sensor interface device; (ii) receive the degradation measurementfrom the analyte sensor via the transceiver interface device of theanalyte sensor and the sensor interface device; (iii) calculate anextent to which the analyte indicator of the analyte sensor has degradedbased at least on the received degradation measurement; (iv) adjust aconversion function based on the calculated extent to which the analyteindicator has degraded; and (v) calculate an analyte level using theadjusted conversion function and the received analyte measurement.

In some embodiments, the analyte sensor may further include an indicatorelement, and the indicator element may include the analyte indicator andthe degradation indicator. In some embodiments, the second detectableproperty does not vary in accordance with the amount or concentration ofthe analyte in the medium.

Further variations encompassed within the systems and methods aredescribed in the detailed description of the invention below.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and form partof the specification, illustrate various, non-limiting embodiments ofthe present invention. In the drawings, like reference numbers indicateidentical or functionally similar elements.

FIG. 1 is a schematic view illustrating an analyte monitoring systemembodying aspects of the present invention.

FIG. 2 is a schematic view illustrating an analyte sensor embodyingaspects of the present invention.

FIG. 3 is a perspective view illustrating elements of an analyte sensorembodying aspects of the present invention.

FIG. 4 is a schematic view illustrating the layout of a semiconductorsubstrate of an analyte sensor embodying aspects of the presentinvention.

FIG. 5 is a chart illustrating non-limiting examples of sensitivityratios correlating an analyte indicator to degradation indicatorsembodying aspects of the present invention.

FIG. 6 is cross-sectional, perspective view of a transceiver embodyingaspects of the invention.

FIG. 7 is an exploded, perspective view of a transceiver embodyingaspects of the invention.

FIG. 8 is a schematic view illustrating a transceiver embodying aspectsof the present invention.

FIG. 9 is a flow chart illustrating a process for detecting andcorrecting for changes to an analyte indicator embodying aspects of thepresent invention.

FIGS. 10-12 are schematic diagrams illustrating non-limiting examples ofstructures of indicator elements 106 embodying aspects of the presentinvention.

FIG. 13 is a graph illustrating a correlation plot of the rates ofdegradation of the indicator and the reference dyes according to onenon-limiting embodiment of the invention.

FIGS. 14A and 14B show fluorimeter readings demonstrating decrease influorescence intensity of indicator molecule (excitation wavelength 380nm) at 2 mM glucose and 50 uM hydrogen peroxide with simultaneousincrease in the fluorescence intensity of Compound A (excitationwavelength 470 nm) at a 1:1 ratio of indicator molecule:Compound Ademonstrating the use of Compound A as a copolymerizable reference dye.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

FIG. 1 is a schematic view of an exemplary analyte monitoring system 50embodying aspects of the present invention. The analyte monitoringsystem 50 may be a continuous analyte monitoring system (e.g., acontinuous glucose monitoring system). In some embodiments, the analytemonitoring system 50 may include one or more of an analyte sensor 100, atransceiver 101, and a display device 107. In some embodiments, theanalyte sensor 100 may be a small, fully subcutaneously implantablesensor that measures the amount or concentration of an analyte (e.g.,glucose) in a medium (e.g., interstitial fluid) of a living animal(e.g., a living human). However, this is not required, and, in somealternative embodiments, the analyte sensor 100 may be a partiallyimplantable (e.g., transcutaneous) sensor or a fully external sensor. Insome embodiments, the transceiver 101 may be an externally worntransceiver (e.g., attached via an armband, wristband, waistband, oradhesive patch). In some embodiments, the transceiver 101 may remotelypower and/or communicate with the sensor 100 to initiate and receive themeasurements (e.g., via near field communication (NFC)). However, thisis not required, and, in some alternative embodiments, the transceiver101 may power and/or communicate with the analyte sensor 100 via one ormore wired connections. In some non-limiting embodiments, thetransceiver 101 may be a smartphone (e.g., an NFC-enabled smartphone).In some embodiments, the transceiver 101 may communicate information(e.g., one or more analyte measurements) wirelessly (e.g., via aBluetooth™ communication standard such as, for example and withoutlimitation Bluetooth Low Energy) to a hand held application running on adisplay device 107 (e.g., smartphone).

FIG. 2 is a schematic view illustrating of an analyte sensor 100embodying aspects of the present invention, and FIG. 3 is a perspectiveview illustrating elements of an analyte sensor 100 embodying aspects ofthe present invention. In some embodiments, the analyte sensor 100 maydetect the presence, amount, and/or concentration of an analyte (e.g.,glucose, oxygen, cardiac markers, low-density lipoprotein (LDL),high-density lipoprotein (HDL), or triglycerides). In some non-limitingembodiments, the analyte sensor 100 may be optical sensors (e.g.,fluorometers). In some embodiments, the analyte sensor 100 may bechemical or biochemical sensors. In some embodiments, the analyte sensor100 may be a radio frequency identification (RFID) device. The analytesensor 100 may be powered by a radio frequency (RF) signal from theexternal transceiver 101.

The analyte sensor 100 may communicate with the external transceiver101. The transceiver 101 may be an electronic device that communicateswith the analyte sensor 100 to power the analyte sensor 100 and/orreceive measurement data (e.g., photodetector and/or temperature sensorreadings) from the analyte sensor 100. The measurement data may includeone or more readings from one or more photodetectors of the analytesensor 100 and/or one or more readings from one or more temperaturesensors of the analyte sensor 100. In some embodiments, the transceiver101 may calculate analyte concentrations from the measurement datareceived from the analyte sensor 100. However, it is not required thatthe transceiver 101 perform the analyte concentration calculationsitself, and, in some alternative embodiments, the transceiver 101 mayinstead convey/relay the measurement data received from the analytesensor 100 to another device for calculation of analyte concentrations.In other alternative embodiments, the analyte sensor 100 may perform theanalyte concentration calculations.

In some embodiments (e.g., embodiments in which the analyte sensor 100is a fully implantable sensing system), the transceiver 101 mayimplement a passive telemetry for communicating with the implantableanalyte sensor 100 via an inductive magnetic link for power and/or datatransfer. In some embodiments, as shown in FIG. 3, the analyte sensor100 may include an inductive element 114, which may be, for example, aferrite based micro-antenna. In some embodiments, as shown in FIG. 3,the inductive element 114 may include a conductor 302 in the form of acoil and a magnetic core 304. In some non-limiting embodiments, the core304 may be, for example and without limitation, a ferrite core. In someembodiments, the inductive element 114 may be connected to analytedetection circuitry of the analyte sensor 100. For example, in someembodiments, where the analyte sensor 100 is an optical sensors, theinductive element 114 may be connected to micro-fluorimeter circuitry(e.g., an application specification integrated circuit (ASIC)) and arelated optical detection system of the analyte sensor 100. In someembodiments, the analyte sensor 100 may not include a battery, and, as aresult, the analyte sensor 100 may rely on the transceiver 101 toprovide power for the analyte sensor 100 of the sensor system 105 and adata link to convey analyte-related data from the analyte sensor 100 totransceiver 101.

In some non-limiting embodiments, the analyte sensor 100 may be apassive, fully implantable multisite sensing system having a small size.For an analyte sensor 100 that is a fully implantable sensing systemhaving no battery power source, the transceiver 101 may provide energyto run the analyte sensor 100 via a magnetic field. In some embodiments,the magnetic transceiver-sensing system link can be considered as“weakly coupled transformer” type. The magnetic transceiver-sensingsystem link may provide energy and a link for data transfer usingamplitude modulation (AM). Although in some embodiments, data transferis carried out using AM, in alternative embodiments, other types ofmodulation may be used. The magnetic transceiver-sensor link may have alow efficiency of power transfer and, therefore, may require relativelyhigh power amplifier to energize the analyte sensor 100 at longerdistances. In some non-limiting embodiments, the transceiver 101 andanalyte sensor 100 may communicate using near field communication (e.g.,at a frequency of 13.56 MHz, which can achieve high penetration throughthe skin and is a medically approved frequency band) for power transfer.However, this is not required, and, in other embodiments, differentfrequencies may be used for powering and communicating with the analytesensor 100.

In some embodiments, as shown in FIG. 7, the transceiver 101 may includean inductive element 103, such as, for example, a coil. The transceiver101 may generate an electromagnetic wave or electrodynamic field (e.g.,by using a coil 103) to induce a current in an inductive element 114 ofthe analyte sensor 100, which powers the analyte sensor 100. Thetransceiver 101 may also convey data (e.g., commands) to the analytesensor 100. For example, in a non-limiting embodiment, the transceiver101 may convey data by modulating the electromagnetic wave used to powerthe analyte sensor 100 (e.g., by modulating the current flowing througha coil of the transceiver 101). The modulation in the electromagneticwave generated by the transceiver 101 may be detected/extracted by theanalyte sensor 100. Moreover, the transceiver 101 may receive data(e.g., measurement information) from the analyte sensor 100. Forexample, in a non-limiting embodiment, the transceiver 101 may receivedata by detecting modulations in the electromagnetic wave generated bythe analyte sensor 100, e.g., by detecting modulations in the currentflowing through the coil 103 of the transceiver 101.

In some non-limiting embodiments, as illustrated in FIG. 2, the analytesensor 100 may include a sensor housing 102 (i.e., body, shell, capsule,or encasement), which may be rigid and biocompatible. In onenon-limiting embodiment, the sensor housing 102 may be a silicon tube.However, this is not required, and, in other embodiments, differentmaterials and/or shapes may be used for the sensor housing 102. In someembodiments, the analyte sensor 100 may include a transmissive opticalcavity. In some non-limiting embodiments, the transmissive opticalcavity may be formed from a suitable, optically transmissive polymermaterial, such as, for example, acrylic polymers (e.g.,polymethylmethacrylate (PMMA)). However, this is not required, and, inother embodiments, different materials may be used for the transmissiveoptical cavity.

In some embodiments, as shown in FIG. 2, the analyte sensor 100 mayinclude an indicator element 106, such as, for example, a polymer graftor hydrogel coated, diffused, adhered, embedded, or grown on or in atleast a portion of the exterior surface of the sensor housing 102. Insome non-limiting embodiments, the sensor housing 102 may include one ormore cutouts or recesses, and the indicator elements 106 may be located(partially or entirely) in the cutouts or recesses. In some embodiments,the indicator element 106 may be porous and may allow the analyte (e.g.,glucose) in a medium (e.g., interstitial fluid) to diffuse into theindicator element 106.

In some embodiments, the indicator element 106 (e.g., polymer graft orhydrogel) of the sensor 100 may include one or more of an analyteindicator 207 and a degradation indicator 209. In some embodiments, theanalyte indicator 207 may exhibit one or more detectable properties(e.g., optical properties) that vary in accordance with (i) the amountor concentration of the analyte in proximity to the indicator element106 and (ii) changes to the analyte indicator 207. In some embodiments,the changes to the analyte indicator 207 may comprise the extent towhich the analyte indicator 207 has degraded. In some non-limitingembodiments, the degradation may be (at least in part) ROS-inducedoxidation. In some embodiments, the analyte indicator 207 may includeone or more analyte indicator molecules (e.g., fluorescent analyteindicator molecules), which may be distributed throughout the indicatorelement 106. In some non-limiting embodiments, the analyte indicator 207may be a phenylboronic-based analyte indicator. However, aphenylboronic-based analyte indicator is not required, and, in somealternative embodiments, the analyte sensor 100 may include a differentanalyte indicator, such as, for example and without limitation, glucoseoxidase-based indicators, glucose dehydrogenase-based indicators, andglucose binding protein-based indicators.

In some embodiments, the degradation indicator 209 may exhibit one ormore detectable properties (e.g., optical properties) that vary inaccordance with changes to the degradation indicator 209. In someembodiments, the degradation indicator 209 is not sensitive to theamount of concentration of the analyte in proximity to the indicatorelement 106. That is, in some embodiments, the one or more detectableproperties exhibited by the degradation indicator 209 do not vary inaccordance with the amount or concentration of the analyte in proximityto the indicator element 106. However, this is not required, and, insome alternative embodiments, the one or more detectable propertiesexhibited by the degradation indicator 209 may vary in accordance withthe amount or concentration of the analyte in proximity to the indicatorelement 106.

In some embodiments, the changes to the degradation indicator 209 maycomprise the extent to which the degradation indicator 209 has degraded.In some embodiments, the degradation may be (at least in part)ROS-induced oxidation. In some embodiments, the degradation indicator209 may include one or more degradation indicator molecules (e.g.,fluorescent degradation indicator molecules), which may be distributedthroughout the indicator element 106. In some non-limiting embodiments,the degradation indicator 209 may be a phenylboronic-based degradationindicator. However, a phenylboronic-based degradation indicator is notrequired, and, in some alternative embodiments, the analyte sensor 100may include a different degradation indicator, such as, for example andwithout limitation, amplex red-based degradation indicators,dichlorodihydrofluorescein-based indicators, dihydrorhodamine-basedindicators, and scopoletin-based degradation indicators.

In some non-limiting embodiments, a degradation indicator molecule maybe a fluorescent probe compound having a wavelength of excitationbetween about 450 nm and about 550 nm, a Stokes shift between about 500nm and about 650 nm, and a half-life of between about 50 days and about150 days. In some non-limiting embodiments, a degradation indicatormolecule may be a compound of formula I:

wherein A, B, C, A′, B′, C′, W, X, Y, and Z represent —CH, wherein thehydrogen may optionally and independently be substituted with an alkylgroup,

R₁ and R₂ are independently selected from one or more vinyl groups,alkyl vinyl groups, acrylamide groups, methacrylamide groups, or otherpolymerizable groups.

Exemplary and non-limiting compounds include the following:

Compounds may be synthesized using the synthetic techniques known in theart such as in “Preparation and use of MitoPY1 for imaging hydrogenperoxide in mitochondria of live cells,” Dickinson, et al. Nat Protoc.2013 June; 8(6): 1249-1259 and U.S. pre-grant publication numberUS2016/0312033 (App. Ser. No. 15/135,788, Yang et al., Oct. 27, 2016),the disclosures of which are incorporated herein by reference in theirentireties.

In some alternative embodiments, the molecules of the degradationindicator 209 may be a compound having a different formula having awavelength of excitation between about 450 nm and about 550 nm, a Stokesshift between about 500 nm and about 650 nm, and a half-life of betweenabout 50 days and about 150 days.

In some non-limiting embodiments, as shown in FIGS. 10-12, the indicatorelement 106 may include one or more polymer backbones 1002. In somenon-limiting embodiments, the polymer backbones 1002 may be polymerchains. In some embodiments, as shown in FIGS. 10 and 11, the indicatorelement 106 may include one or more analyte indicator molecules A andone or more degradation indicator molecules D. In some embodiments, asshown in FIGS. 10 and 11, the analyte indicator molecules A anddegradation indicator molecules D may be monomers polymerizedindividually to a polymer backbone 1002. In some non-limitingembodiments, the indicator element 106 may include an equal number ofanalyte indicator molecules A and degradation indicator molecules D (seeFIG. 10) or a different number of analyte indicator molecules A anddegradation indicator molecules D (see FIG. 11). In some embodiments,there may ratio of analyte indicator molecules A to degradationindicator molecules D, such as, for example and without limitation, 1:1as shown in FIG. 10, 2:1 as shown in FIG. 11, 1:2, 3:1, 5:1, 10:1, etc.

In some alternative embodiments, as shown in FIG. 12, one or moredegradation indicator molecules D may be chemically bonded to an analyteindicator molecule A (e.g., via a covalent bond), and the analyteindicator molecule A may be chemically bonded to a polymer backbone1002. In one non-limiting alternative embodiment, the analyte indicatormolecules A and degradation indicator molecules D may be monomers, andthe analyte indicator molecules A may be polymerized to the polymerbackbone 1002. In some other alternative embodiments, one or moreanalyte indicator molecules A may be chemically bonded to a degradationindicator molecules D, and the degradation indicator molecule D may bechemically bonded to a polymer backbone 1002. In one non-limitingalternative embodiment, the analyte indicator molecules A anddegradation indicator molecules D may be monomers, and the degradationindicator molecules D may be polymerized to the polymer backbone 1002.

In some embodiments, the analyte sensor 100 may measure changes to theanalyte indicator 207 indirectly using the degradation indicator 209,which may by sensitive to degradation by reactive oxygen species (ROS)but not sensitive to the analyte. In some embodiments, the degradationindicator 207 may have one or more optical properties that change withextent of oxidation and may be used as a reference dye for measuring andcorrecting for extent of oxidation of the analyte indicator. In someembodiments, the extent to which the degradation indicator 209 hasdegraded may correspond to the extent to which the analyte indicator 207has degraded. For example, in some non-limiting embodiments, the extentto which the degradation indicator 209 has degraded may be proportionalto the extent to which the analyte indicator 207 has degraded. In somenon-limiting embodiments, the extent to which the analyte indicator 207has degraded may be calculated based on the extent to which thedegradation indicator 209 has degraded. In some embodiments, the analytemonitoring system 50 may correct for changes in the analyte indicator207 using an empiric correlation established through laboratory testing.

In some embodiments, as shown in FIG. 2, the analyte sensor 100 mayinclude one or more first light sources 108 that emit first excitationlight 329 over a range of wavelengths that interact with the analyteindicator 207 in the indicator element 106. In some non-limitingembodiments, the first excitation light 329 may be ultraviolet (UV)light. In some embodiments, the analyte sensor 100 may include one ormore light sources 227 that emit second excitation light 330 over arange of wavelengths that interact with the degradation indicator 209 inthe indicator element 106. In some non-limiting embodiments, the secondexcitation light 330 may be blue light.

In some embodiments, as shown in FIG. 2, the analyte sensor 100 may alsoinclude one or more photodetectors 224, 226, 228 (e.g., photodiodes,phototransistors, photoresistors, or other photosensitive elements). Insome embodiments, the analyte sensor 100 may include one or more signalphotodetectors 224 sensitive to first emission light 331 (e.g.,fluorescent light) emitted by the analyte indicator 207 of the indicatorelement 106 such that a signal generated by a photodetector 224 inresponse thereto that is indicative of the level of first emission light331 of the analyte indicator 207 and, thus, the amount of analyte ofinterest (e.g., glucose). In some non-limiting embodiments, the analytesensor 100 may include one or more reference photodetectors 226 may besensitive to first excitation light 329 that may be reflected from theindicator element 106. In some embodiments, the analyte sensor 100 mayinclude one or more degradation photodetectors 228 sensitive to secondemission light 332 (e.g., fluorescent light) emitted by the degradationindicator 209 of the indicator element 106 such that a signal generatedby a photodetector 228 in response thereto that is indicative of thelevel of second emission light 332 of the degradation indicator 209 and,thus, the amount of degradation (e.g., oxidation). In some non-limitingembodiments, the one or more signal photodetectors 224 may be sensitiveto second excitation light 330 that may be reflected from the indicatorelement 106. In this way, the one or more signal photodetectors 224 mayact as reference photodetectors when the one or more light sources 227are emitting second excitation light 330.

In some embodiments, the first excitation light 329 may be over a firstwavelength range, and the second excitation light 330 over a secondwavelength range, which may different than the first wavelength range.In some non-limiting embodiments, the first and second wavelength rangesdo not overlap, but this not required, and, in some alternativeembodiments, the first and second wavelength ranges may overlap. In someembodiments, the first emission light 331 may be over a third wavelengthrange, and the second emission light 332 may be over a fourth wavelengthrange, which may be different than the third wavelength range. In somenon-limiting embodiments, the third and fourth wavelength ranges do notoverlap, but this is not required, and, in some alternative embodiments,the third and fourth wavelength ranges may overlap. In some embodiments,the first and third wavelength ranges may be different. In somenon-limiting embodiments, the first and third wavelength ranges do notoverlap, but this is not required, and, in some alternative embodiments,the first and third wavelength ranges may overlap. In some embodiments,the second and fourth wavelength ranges may be different. In somenon-limiting embodiments, the second and fourth wavelength ranges do notoverlap, but this is not required, and, in some alternative embodiments,the second and fourth wavelength ranges may overlap. In somenon-limiting embodiments, the second and third wavelength ranges mayoverlap.

In some embodiments, one or more of the photodetectors 224, 226, 228 maybe covered by one or more filters that allow only a certain subset ofwavelengths of light to pass through and reflect (or absorb) theremaining wavelengths. In some non-limiting embodiments, one or morefilters on the one or more signal photodetectors 224 may allow only asubset of wavelengths corresponding to first emission light 331 and/orthe reflected second excitation light 330. In some non-limitingembodiments, one or more filters on the one or more referencephotodetectors 226 may allow only a subset of wavelengths correspondingto the reflected first excitation light 329. In some non-limitingembodiments, one or more filters on the one or more degradationphotodetectors 228 may allow only a subset of wavelengths correspondingto second emission light 332.

In some embodiments, the degradation indicator 209 may be used as areference dye for measuring and correcting for extent of oxidation ofthe analyte indicator 207. In some embodiments, the analyte monitoringsystem 50 may correct for changes in the analyte indicator 207 using anempiric correlation established through laboratory testing. FIG. 5 is achart illustrating non-limiting examples of sensitivity ratioscorrelating an analyte indicator 207 to a degradation indicator 209. Insome embodiments, as shown by the sensitivity ratio 1 in FIG. 5, thedegradation indicator 209 may be more sensitive to oxidation than theanalyte indicator 207. However, this is not required, and, in somealternative embodiments, as shown by the sensitivity ratio 2 in FIG. 5,the degradation indicator 207 may be less sensitive to oxidation thanthe analyte indicator 207. In some other alternative embodiments, thedegradation indicator 209 and analyte indicator 207 may be equallysensitive to oxidation.

In some embodiments, the substrate 112 may be a circuit board (e.g., aprinted circuit board (PCB) or flexible PCB) on which one or more of thecircuit components 111 (e.g., analog and/or digital circuit components)may be mounted or otherwise attached. However, in some alternativeembodiments, the substrate 112 may be a semiconductor substrate havingone or more of the circuit components 111 fabricated therein. Forinstance, the fabricated circuit components may include analog and/ordigital circuitry. Also, in some embodiments in which the substrate 112is a semiconductor substrate, in addition to the circuit componentsfabricated in the semiconductor substrate, circuit components may bemounted or otherwise attached to the semiconductor substrate. In otherwords, in some semiconductor substrate embodiments, a portion or all ofthe circuit components 111, which may include discrete circuit elements,an integrated circuit (e.g., an application specific integrated circuit(ASIC)) and/or other electronic components (e.g., a non-volatilememory), may be fabricated in the semiconductor substrate with theremainder of the circuit components 111 is secured to the semiconductorsubstrate, which may provide communication paths between the varioussecured components.

In some embodiments, the analyte sensor 100 may include one or morelight sources 108, 227, and one or more of the light sources 108, 227may be mounted on or fabricated within in the substrate 112. In someembodiments, the analyte sensor 100 may include one or morephotodetectors 224, 226, 228, and one or more of the photodetectors 224,226, 228 may be mounted on or fabricated in the substrate 112. In somenon-limiting embodiments, one or more light sources 108, 227 may bemounted on the substrate 112, one or more photodetectors may befabricated within the substrate 112, and all or a portion of the circuitcomponents 111 may be fabricated within the substrate 112.

In some embodiments, the one or more of the indicator element 106, lightsource(s) 108, 227, photodetectors 224, 226, 228, circuit components111, and substrate 112 of the analyte sensor 100 may include some or allof the features described in one or more of U.S. application Ser. No.13/761,839, filed on Feb. 7, 2013, U.S. application Ser. No. 13/937,871,filed on Jul. 9, 2013, U.S. application Ser. No. 13/650,016, filed onOct. 11, 2012, and U.S. application Ser. No. 14/142,017, filed on Dec.27, 2013, all of which are incorporated by reference in theirentireties. Similarly, the structure, function, and/or features of thesensor housing 102, analyte sensor 100, and/or transceiver 101 may be asdescribed in one or more of U.S. application Ser. Nos. 13/761,839,13/937,871, 13/650,016, and 14/142,017. For instance, the sensor housing102 may have one or more hydrophobic, hydrophilic, opaque, and/or immuneresponse blocking membranes or layers on the exterior thereof.

Although in some embodiments, as illustrated in FIG. 1, the analytesensor 100 may be a fully implantable sensor, this is not required, and,in some alternative embodiments, the analyte sensor 100 may be atranscutaneous sensing system having a wired connection to thetransceiver 101. For example, in some alternative embodiments, theanalyte sensor 100 may be located in or on a transcutaneous needle(e.g., at the tip thereof). In these embodiments, instead of wirelesslycommunicating using inductive elements 103 and 114, the analyte sensor100 and transceiver 101 may communicate using one or more wiresconnected between the transceiver 101 and the transceiver transcutaneousneedle that includes the analyte sensor 100. For another example, insome alternative embodiments, the analyte sensor 100 may be located in acatheter (e.g., for intravenous blood glucose monitoring) and maycommunicate (wirelessly or using wires) with the transceiver 101.

In some embodiments, the analyte sensor 100 may include a transceiverinterface device. In some embodiments, the transceiver interface devicemay include the antenna (e.g., inductive element 114) of the analytesensor 100. In some of the transcutaneous embodiments where there existsa wired connection between the analyte sensor 100 and the transceiver101, the transceiver interface device may include the wired connection.

FIGS. 6 and 7 are cross-sectional and exploded views, respectively, of anon-limiting embodiment of the transceiver 101, which may be included inthe analyte monitoring system 50 illustrated in FIG. 1. As illustratedin FIG. 7, in some non-limiting embodiments, the transceiver 101 mayinclude a graphic overlay 204, front housing 206, button 208, printedcircuit board (PCB) assembly 210, battery 212, gaskets 214, antenna 103,frame 218, reflection plate 216, back housing 220, ID label 222, and/orvibration motor 928. In some non-limiting embodiments, the vibrationmotor 928 may be attached to the front housing 206 or back housing 220such that the battery 212 does not dampen the vibration of vibrationmotor 928. In a non-limiting embodiment, the transceiver electronics maybe assembled using standard surface mount device (SMD) reflow and soldertechniques. In one embodiment, the electronics and peripherals may beput into a snap together housing design in which the front housing 206and back housing 220 may be snapped together. In some embodiments, thefull assembly process may be performed at a single external electronicshouse. However, this is not required, and, in alternative embodiments,the transceiver assembly process may be performed at one or moreelectronics houses, which may be internal, external, or a combinationthereof. In some embodiments, the assembled transceiver 101 may beprogrammed and functionally tested. In some embodiments, assembledtransceivers 101 may be packaged into their final shipping containersand be ready for sale.

In some embodiments, as illustrated in FIGS. 6 and 7, the antenna 103may be contained within the housing 206 and 220 of the transceiver 101.In some embodiments, the antenna 103 in the transceiver 101 may be smalland/or flat so that the antenna 103 fits within the housing 206 and 220of a small, lightweight transceiver 101. In some embodiments, theantenna 103 may be robust and capable of resisting various impacts. Insome embodiments, the transceiver 101 may be suitable for placement, forexample, on an abdomen area, upper-arm, wrist, or thigh of a patientbody. In some non-limiting embodiments, the transceiver 101 may besuitable for attachment to a patient body by means of a biocompatiblepatch. Although, in some embodiments, the antenna 103 may be containedwithin the housing 206 and 220 of the transceiver 101, this is notrequired, and, in some alternative embodiments, a portion or all of theantenna 103 may be located external to the transceiver housing. Forexample, in some alternative embodiments, antenna 103 may wrap around auser's wrist, arm, leg, or waist such as, for example, the antennadescribed in U.S. Pat. No. 8,073,548, which is incorporated herein byreference in its entirety.

FIG. 8 is a schematic view of an external transceiver 101 according to anon-limiting embodiment. In some embodiments, the transceiver 101 mayhave a connector 902, such as, for example, a Micro-Universal Serial Bus(USB) connector. The connector 902 may enable a wired connection to anexternal device, such as a personal computer (e.g., personal computer109) or a display device 107 (e.g., a smartphone).

The transceiver 101 may exchange data to and from the external devicethrough the connector 902 and/or may receive power through the connector902. The transceiver 101 may include a connector integrated circuit (IC)904, such as, for example, a USB-IC, which may control transmission andreceipt of data through the connector 902. The transceiver 101 may alsoinclude a charger IC 906, which may receive power via the connector 902and charge a battery 908 (e.g., lithium-polymer battery). In someembodiments, the battery 908 may be rechargeable, may have a shortrecharge duration, and/or may have a small size.

In some embodiments, the transceiver 101 may include one or moreconnectors in addition to (or as an alternative to) Micro-USB connector904. For example, in one alternative embodiment, the transceiver 101 mayinclude a spring-based connector (e.g., Pogo pin connector) in additionto (or as an alternative to) Micro-USB connector 904, and thetransceiver 101 may use a connection established via the spring-basedconnector for wired communication to a personal computer (e.g., personalcomputer 109) or a display device 107 (e.g., a smartphone) and/or toreceive power, which may be used, for example, to charge the battery908.

In some embodiments, the transceiver 101 may have a wirelesscommunication IC 910, which enables wireless communication with anexternal device, such as, for example, one or more personal computers(e.g., personal computer 109) or one or more display devices 107 (e.g.,a smartphone). In one non-limiting embodiment, the wirelesscommunication IC 910 may employ one or more wireless communicationstandards to wirelessly transmit data. The wireless communicationstandard employed may be any suitable wireless communication standard,such as an ANT standard, a Bluetooth standard, or a Bluetooth Low Energy(BLE) standard (e.g., BLE 4.0). In some non-limiting embodiments, thewireless communication IC 910 may be configured to wirelessly transmitdata at a frequency greater than 1 gigahertz (e.g., 2.4 or 5 GHz). Insome embodiments, the wireless communication IC 910 may include anantenna (e.g., a Bluetooth antenna). In some non-limiting embodiments,the antenna of the wireless communication IC 910 may be entirelycontained within the housing (e.g., housing 206 and 220) of thetransceiver 101. However, this is not required, and, in alternativeembodiments, all or a portion of the antenna of the wirelesscommunication IC 910 may be external to the transceiver housing.

In some embodiments, the transceiver 101 may include a display interfacedevice, which may enable communication by the transceiver 101 with oneor more display devices 107. In some embodiments, the display interfacedevice may include the antenna of the wireless communication IC 910and/or the connector 902. In some non-limiting embodiments, the displayinterface device may additionally include the wireless communication IC910 and/or the connector IC 904.

In some embodiments, the transceiver 101 may include voltage regulators912 and/or a voltage booster 914. The battery 908 may supply power (viavoltage booster 914) to radio-frequency identification (RFID) reader IC916, which uses the inductive element 103 to convey information (e.g.,commands) to the sensor 101 and receive information (e.g., measurementinformation) from the sensor 100. In some non-limiting embodiments, thesensor 100 and transceiver 101 may communicate using near fieldcommunication (NFC) (e.g., at a frequency of 13.56 MHz). In theillustrated embodiment, the inductive element 103 is a flat antenna. Insome non-limiting embodiments, the antenna may be flexible. However, asnoted above, the inductive element 103 of the transceiver 101 may be inany configuration that permits adequate field strength to be achievedwhen brought within adequate physical proximity to the inductive element114 of the sensor 100. In some embodiments, the transceiver 101 mayinclude a power amplifier 918 to amplify the signal to be conveyed bythe inductive element 103 to the sensor 100.

In some embodiments, the transceiver 101 may include a peripheralinterface controller (PIC) controller 920 and memory 922 (e.g., Flashmemory), which may be non-volatile and/or capable of beingelectronically erased and/or rewritten. The PIC controller 920 maycontrol the overall operation of the transceiver 101. For example, thePIC controller 920 may control the connector IC 904 or wirelesscommunication IC 910 to transmit data via wired or wirelesscommunication and/or control the RFID reader IC 916 to convey data viathe inductive element 103. The PIC controller 920 may also controlprocessing of data received via the inductive element 103, connector902, or wireless communication IC 910.

In some embodiments, the transceiver 101 may include a sensor interfacedevice, which may enable communication by the transceiver 101 with asensor 100. In some embodiments, the sensor interface device may includethe inductive element 103. In some non-limiting embodiments, the sensorinterface device may additionally include the RFID reader IC 916 and/orthe power amplifier 918. However, in some alternative embodiments wherethere exists a wired connection between the sensor 100 and thetransceiver 101 (e.g., transcutaneous embodiments), the sensor interfacedevice may include the wired connection.

In some embodiments, the transceiver 101 may include a display 924(e.g., liquid crystal display and/or one or more light emitting diodes),which PIC controller 920 may control to display data (e.g., analyteconcentration values). In some embodiments, the transceiver 101 mayinclude a speaker 926 (e.g., a beeper) and/or vibration motor 928, whichmay be activated, for example, in the event that an alarm condition(e.g., detection of a hypoglycemic or hyperglycemic condition) is met.The transceiver 101 may also include one or more additional sensors 930,which may include an accelerometer and/or temperature sensor, that maybe used in the processing performed by the PIC controller 920.

FIG. 9 illustrates non-limiting embodiment of an analyte monitoringprocess 950 that may be performed by the analyte monitoring system 50.In some embodiments, the process 950 may detect and correct for changesto the analyte indicator 207. In some embodiments, the process 950 mayinclude a step 952 in which the analyte monitoring system 50 measures ananalyte signal. In some embodiments, the step 952 may include thetransceiver 101 conveying an analyte measurement command to the analytesensor 100. In some embodiments, the step 952 may include the analytesensor 100, in response to receiving and decoding the analytemeasurement command, using the first light source 108 to emit firstexcitation light 329 to the indicator element 106. The analyte indicator207 of the indicator element 106 may receive the first excitation light329 and emit first emission light 331. The signal photodetector 224 mayreceive the first emission light 331 and generate an analyte measurementsignal based on the amount of first emission light 331 received by thesignal photodetector 224. In some embodiments, the step 952 may includethe analyte sensor 100 using the reference photodetector 226 to receivefirst excitation light 329 that was reflected from the indicator element106 and generate a reference signal indicative of the amount ofreflected first excitation light 329 received by the referencephotodetector 226.

In some embodiments, the process 950 may include a step 954 in which theanalyte monitoring system 50 measures a degradation signal. In someembodiments, the step 954 may include the transceiver 101 conveying adegradation measurement command to the analyte sensor 100. In someembodiments, the step 954 may include the analyte sensor 100, inresponse to receiving and decoding the degradation measurement command,using the second light source 227 to emit second excitation light 330 tothe indicator element 106. The degradation indicator 209 of theindicator element 106 may receive the second excitation light 330 andemit second emission light 332. The degradation photodetector 228 mayreceive the second emission light 332 and generate an analytemeasurement signal based on the amount of second emission light 332received by the degradation photodetector 228. In some embodiments, thestep 954 may include the analyte sensor 100 using the signalphotodetector 224 to receive second excitation light 330 that wasreflected from the indicator element 106 and generate a reference signalindicative of the amount of reflected second excitation light 330received by the signal photodetector 224.

In some alternative embodiments, the step 954 may not include conveyinga degradation measurement command to the analyte sensor 100, and theanalyte sensor 100 may use the second light source 227 to emit thesecond excitation light 330 to the indicator element 106 in response toreceiving and decoding an analyte measurement command (instead of inresponse to receiving and decoding a degradation measurement command).In some alternative embodiments, steps 952 and 954 may be performedsimultaneously, and the analyte sensor 100 may use the first and secondlight sources 108, 227 to emit simultaneously the first and secondexcitation lights 329, 330 to the indicator element 106. In somealternative embodiments, step 954 may be performed before step 952.

In some embodiments, the process 950 may include a step 956 in which theanalyte monitoring system 50 calculates changes in the analyte indicator207. In some embodiments, the step 956 may include the transceiver 101receiving sensor data from the analyte sensor 100. In some embodiments,the sensor data may include one or more of an analyte measurement, afirst reference measurement, a degradation measurement, a secondreference measurement, and a temperature measurement. In someembodiments, the analyte measurement may correspond to the amount offirst emission light 331 received by the signal photodetector 224, thefirst reference measurement may correspond to the amount of reflectedfirst excitation light 329 received by the reference photodetector 226,the degradation measurement may correspond to the amount of secondemission light 332 received by the degradation photodetector 228, andthe second reference measurement may correspond to the amount ofreflected second excitation light 330 received by the signalphotodetector 224. In some alternative embodiments, one or more of theanalyte measurement and the first reference measurement may be receivedduring step 952, and one or more of the degradation measurement and thesecond reference measurement may be received during step 954.

In some embodiments, the step 956 may include the transceiver 101 (e.g.,the microcontroller 910 of the transceiver 101) determining the extentthat the analyte indicator 207 has degraded based at least on thereceived degradation measurement. In some non-limiting embodiments, thestep 956 may include the transceiver 101 determining (i) the extent thatthe degradation indicator 209 has been degraded based on the receiveddegradation measurement and (ii) the extent that the analyte indicator207 has been degraded based on the determined extent to which thedegradation indicator 209 has been degraded. In some non-limitingembodiments, the transceiver 101 may additionally or alternatively useone or more previous degradation measurements and/or one or moreprevious determinations of the extent to which the degradation indicator209 has degraded to determine the extent to which the analyte indicator207 has degraded.

In some embodiments, the process 950 may include a step 958 in which theanalyte monitoring system 50 corrects for the calculated changes to theanalyte indicator 207. In some non-limiting embodiments, the transceiver101 (e.g., the microcontroller 910 of the transceiver 101) may correctfor the calculated changes to the analyte indicator 207 by adjusting theconversion function used to calculate an analyte level based on ananalyte measurement. In some embodiments, adjusting the conversionfunction may include adjusting one or more parameters of the conversionfunction. In some embodiments, in step 958, the transceiver 101 mayadditionally or alternatively adjust the conversion function based onthe first reference measurement, which may be indicative of in-vivohydration of the indicator element 106 and/or wound healing kinetics. Insome embodiments, in step 958, the transceiver 101 may additionally oralternatively adjust the conversion function based on the secondreference measurement, which may be a measurement of the opacity of theindicator element 106 in the wavelength range of the first emissionlight 331.

In some embodiments, the process 950 may include a step 960 in which theanalyte monitoring system 50 calculates an analyte level (e.g., ananalyte concentration). In some embodiments, in step 960, thetransceiver 101 (e.g., the microcontroller 910 of the transceiver 101)may calculate the analyte level using at least the adjusted conversionfunction and the analyte measurement. In some embodiments, thetransceiver 101 may additionally use the temperature measurement tocalculate the analyte level.

In some embodiments, the process 950 may include a step 962 in which theanalyte monitoring system 50 displays the calculated analyte level. Insome embodiments, in step 962, the transceiver 101 may display theanalyte level on the display 924. In some embodiments, in step 962, thetransceiver 101 may additionally or alternatively convey the calculatedanalyte level to the display device 107, and the display device 107 mayadditionally or alternatively convey the calculated analyte level.

EXAMPLE

Compound A was copolymerized with an indicator molecule onto a hydrogel.Methods of copolymerizing are described in U.S. Pat. No. 7,060,503(Colvin) and U.S. Pat. No. 9,778,190 (Huffstetler et al.), which areincorporated by reference in their entireties.

Initial characterization followed by subsequent oxidation test helped inunderstanding the degradation kinetics of both the reference dye(Compound A) and the indicator as shown in FIGS. 14A and 14B. Initialfluorimeter work was performed with a 1:1 ratio of indicator(TFM):Compound A demonstrating the use of Compound A as acopolymerizable reference dye. The plots in FIG. 14A and FIG. 14Bdemonstrate decreases in fluorescence intensity of indicator molecule(excitation wavelength 380 nm) at 2 mM glucose and 50 uM hydrogenperoxide with simultaneous increase in the fluorescence intensity ofCompound A (excitation wavelength 470 nm). TFM has a chemical name of9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracenesodium salt.

An in vivo study was performed in 18 female guinea pigs using mocksensors having a 1:1 ratio of the copolymerized indicator:Compound A ina hydrogel thereon were implanted into the guinea pigs to assessperformance of Compound A in response to in vivo oxidation and itscorrelation to degradation of the indicator molecule. Implantation wasexecuted subcutaneously in the back of each guinea pig (2 samples perguinea pig) with the Senseonics implant tool kit according to theimplant training file. The subjects were divided into three groups ofexplant time points, which were at day 30, 60 and 90. Once the sampleswere explanted, they were washed and disinfected using ENZOL® enzymaticdetergent and glutaraldehyde solution. The explanted samples were thenanalyzed by fluorimetry to evaluate fluorescence intensity change inCompound A and to correlate % increase in Compound A intensity to %modulation loss in the indicator.

An in vitro study was performed as follows: An initial 0-18 modulationswere done prior to oxidation test to collect the initial modulationdata. A known concentration of hydrogen peroxide was used todeliberately oxidize the sensor partially. After partial oxidation, the0-18 modulations were performed again to collect the modulation data andrecord the loss in modulation. This procedure was repeated for 3-5cycles where the same sensor undergoes further partial oxidation and ateach oxidized step a 0-18 modulation data was collected. A correlationplot of the rates of degradation of both indicator and the reference dyeis shown in FIG. 13.

In explant analysis of the samples, the samples showed a strongcorrelation between the in vitro and in vivo oxidized samples. Thiscorrelation is useful for determining the amount of modulation left atthe signal channel by analyzing the amount of the indicator dyeoxidation thereby reducing the number of calibrations that areperformed.

Embodiments of the present invention have been fully described abovewith reference to the drawing figures. Although the invention has beendescribed based upon these preferred embodiments, it would be apparentto those of skill in the art that certain modifications, variations, andalternative constructions could be made to the described embodimentswithin the spirit and scope of the invention. For example, although theembodiments of the invention in which the analyte indicator 207 anddegradation indicator 209 are distributed throughout the same indicatorelement 106, this is not required. In some alternative embodiments, theanalyte sensor 100 may include a first indicator element that includesthe analyte indicator 207 and a second indicator element that includesthe degradation indicator 209. In these alternative embodiments, theanalyte indicator 207 and the degradation indicator 209 may be spatiallyseparated from one another.

What is claimed is:
 1. An analyte sensor for measurement of an analytein a medium within a living animal, the analyte sensor comprising: ananalyte indicator configured to exhibit a first detectable property thatvaries in accordance with (i) an amount or concentration of the analytein the medium and (ii) an extent to which the analyte indicator hasdegraded; a degradation indicator configured to exhibit a seconddetectable property that varies in accordance with an extent to whichthe degradation indicator has degraded, wherein the extent to which thedegradation indicator has degraded corresponds to the extent to whichthe analyte indicator has degraded; and sensor elements configured togenerate (i) an analyte measurement based on the first detectableproperty exhibited by the analyte indicator and (ii) a degradationmeasurement based on the second detectable property exhibited by thedegradation indicator.
 2. The analyte sensor of claim 1, wherein theextent to which the degradation indicator has degraded is proportionalto the extent to which the analyte indicator has degraded.
 3. Theanalyte sensor of claim 1, wherein degradation to the analyte indicatorcomprises reactive oxidation species (ROS)-induced oxidation, anddegradation to the degradation indicator comprises ROS-inducedoxidation.
 4. The analyte sensor of claim 1, wherein the analyteindicator is a phenylboronic-based analyte indicator.
 5. The analytesensor of claim 1, wherein the degradation indicator is aphenylboronic-based degradation indicator.
 6. The analyte sensor ofclaim 1, further comprising an indicator element comprising the analyteindicator and the degradation indicator.
 7. The analyte sensor of claim6, wherein the analyte indicator comprises analyte indicator moleculesdistributed throughout the indicator element, and the degradationindicator comprises degradation indicator molecules distributedthroughout the indicator element.
 8. The analyte sensor of claim 1,wherein the sensor elements comprise: a first light source configured toemit first excitation light to the analyte indicator; and a firstphotodetector configured to receive first emission light emitted by theanalyte indicator and output the analyte measurement, wherein theanalyte measurement is indicative of an amount of first emission lightreceived by the first photodetector.
 9. The analyte sensor of claim 1,wherein the sensor elements comprise: a second light source configuredto emit second excitation light to the degradation indicator; and asecond photodetector configured to receive second emission light emittedby the degradation indicator and output the degradation measurement,wherein the degradation measurement is indicative of an amount of secondemission light received by the second photodetector.
 10. The analytesensor of claim 9, wherein the first photodetector is configured toreceive second excitation light reflected from the indicator element andoutput a first reference signal indicative of an amount of reflectedsecond excitation light received by the first photodetector.
 11. Theanalyte sensor of claim 9, wherein the sensor elements comprise a thirdphotodetector configured to receive first excitation light reflectedfrom the indicator element and output a second reference signalindicative of an amount of reflected first excitation light received bythe third photodetector.
 12. The analyte sensor of claim 1, wherein thesecond detectable property does not vary in accordance with the amountor concentration of the analyte in the medium.
 13. The analyte sensor ofclaim 1, wherein the degradation indicator is a compound of formula I:

wherein A, B, C, A′, B′, C′, W, X, Y, and Z represent —CH, wherein thehydrogen of —CH may optionally and independently be substituted with analkyl group; R₁ and R₂ are independently selected from one or more vinylgroups, alkyl vinyl groups, acrylamide groups, methacrylamide groups, orother polymerizable groups.
 14. The analyte sensor of claim 1, whereinthe degradation indicator is a molecule selected from the following:


15. A method comprising: using an analyte indicator of an analyte sensorto measure an amount or concentration of an analyte in a medium; using adegradation indicator of the analyte sensor to measure an extent towhich the degradation indicator has degraded; using a sensor interfacedevice of a transceiver to receive from the analyte sensor an analytemeasurement indicative of the amount or concentration of the analyte inthe medium; using the sensor interface device of the transceiver toreceive from the analyte sensor a degradation measurement indicative ofthe extent to which the degradation indicator has degraded; using acontroller of the transceiver to calculate an extent to which theanalyte indicator of the analyte sensor has degraded based at least onthe received degradation measurement; using the controller of thetransceiver to adjust a conversion function based on the calculatedextent to which the analyte indicator has degraded; using the controllerof the transceiver to calculate an analyte level using the adjustedconversion function and the received analyte measurement; and displayingthe calculated analyte level.
 16. The method of claim 15, wherein thedegradation indicator is a compound of formula I:

wherein A, B, C, A′, B′, C′, W, X, Y, and Z represent —CH, wherein thehydrogen of —CH may optionally and independently be substituted with analkyl group; R₁ and R₂ are independently selected from one or more vinylgroups, alkyl vinyl groups, acrylamide groups, methacrylamide groups, orother polymerizable groups.
 17. The method of claim 15, wherein thedegradation indicator is a molecule selected from the following:


18. An analyte monitoring system comprising: an analyte sensorincluding: an analyte indicator configured to exhibit a first detectableproperty that varies in accordance with (i) an amount or concentrationof an analyte in a medium and (ii) an extent to which the analyteindicator has degraded; a degradation indicator configured to exhibit asecond detectable property that varies in accordance with an extent towhich the degradation indicator has degraded; sensor elements configuredto generate (i) an analyte measurement based on the first detectableproperty exhibited by the analyte indicator and (ii) a degradationmeasurement based on the second detectable property exhibited by thedegradation indicator; and a transceiver interface device; and atransceiver including: a sensor interface device; and a controllerconfigured to: (i) receive the analyte measurement from the analytesensor via the transceiver interface device of the analyte sensor andthe sensor interface device; (ii) receive the degradation measurementfrom the analyte sensor via the transceiver interface device of theanalyte sensor and the sensor interface device; (iii) calculate anextent to which the analyte indicator of the analyte sensor has degradedbased at least on the received degradation measurement; (iv) adjust aconversion function based on the calculated extent to which the analyteindicator has degraded; (v) calculate an analyte level using theadjusted conversion function and the received analyte measurement. 19.The analyte monitoring system of claim 18, wherein the analyte sensorfurther includes an indicator element comprising the analyte indicatorand the degradation indicator.
 20. The analyte monitoring system ofclaim 18, wherein the second detectable property does not vary inaccordance with the amount or concentration of the analyte in themedium.
 21. The analyte monitoring system of claim 18, wherein thedegradation indicator is a compound of formula I:

wherein A, B, C, A′, B′, C′, W, X, Y, and Z represent —CH, wherein thehydrogen of —CH may optionally and independently be substituted with analkyl group; R₁ and R₂ are independently selected from one or more vinylgroups, alkyl vinyl groups, acrylamide groups, methacrylamide groups, orother polymerizable groups.
 22. The analyte sensor of any one of claim18, wherein the degradation indicator is a molecule selected from thefollowing: